Patients and methods: This study is a randomized prospective study. Seventy eyes with DME were divided into two groups (each containing 35 eyes). Eyes in group I were treated with intravitreal injection of 2 mg/0.05 mL aflibercept and eyes in group II were treated with intravitreal injection of 0.5 mg/0.1 mL ranibizumab. All the eyes had three successive injections as a loading dose (with 1 month interval), and then the patients were followed up monthly for 12 months. The outcomes of the study were visual acuity, central macular thickness (CMT), and the number of re-injections of the drug.
Abstract: Diabetic retinopathy is the leading cause of blindness among individuals of working age in industrialized nations, with most of the vision loss resulting from diabeticmacularedema (DME). The formation of DME depends on the action of several growth factors and inflammatory mediators, but vascular endothelial growth factor (VEGF) appears to be critical for breaking down the blood-retinal barrier and promoting the accumulation of macularedema. Laser photocoagulation has been the standard-of-care for three decades, and although it stabilizes vision, significant gains in visual acuity after treatment are unusual. Several VEGF inhibitors (pegaptanib, aflibercept, and ranibizumab) have been initially developed and tested for the treatment of age-related macular degeneration and subsequently for DME. In Phase I, II, and III trials for DME, ranibizumab has been shown to be superior to macular laser photocoagulation and intraocular triamcinolone acetonide injections for improving visual acuity and drying the macula. As a result, ranibizumab is the only anti-VEGF drug that has been approved by the United States Food and Drug Administration for the treatment of DME. Most experts now consider intravitreal anti-VEGF therapy to be standard-of-care for DME involving the fovea.
Diabeticmacularedema (DME), is one of the most common causes of visual impairment in the diabetic patients . The worldwide prevalence of diabetes is estimated to rise to 366 million by 2030 . The 10-year incidence of macularedema in patients with type 2 diabetes was up to 14%, and 29% of type 1 progressed into DME over a 25-year period [3,4]. Hence, finding a safe and effective treatment of DME becomes urgent. Despite the high prevalence of DME, there is no definite treatment because of its complicated pathophysiologic mechanism, which is still not fully understood. However, there is no single modality that has been shown to be superior. The Early TreatmentDiabetic Retinopathy Study (EDTRS) showed that macular laser photocoagulation (MPC) is effective in reducing the risk of visual loss by approximately 50% in eyes with clinically significant macularedema . However, unsatisfactory outcomes are frequent, and 12% treated eyes developed moderate visual loss. Moreover, about 15% patients fall into the category of refractory DME and do not respond to repeated laser treatments. This shows that in spite of laser being the gold standard treatment of DME, some patients do not respond to laser . Various modalities of treatment are currently being tried in the management of persistent; laser refractory DME such as supplemental laser, intravitreal steroid injection, and anti-vascular endothelial growth factor (anti-VEGF) injection .
Abstract: Diabeticmacularedema (DME) resembles a chronic, low-grade inflammatory reac- tion, and is characterized by blood–retinal barrier (BRB) breakdown and retinal capillary leakage. Corticosteroids are of therapeutic benefit because of their anti-inflammatory, antiangiogenic, and BRB-stabilizing properties. Delivery modes include periocular and intravitreal (via pars plana) injection. To offset the short intravitreal half-life of corticosteroid solutions (~3 hours) and the need for frequent intravitreal injections, sustained-release intravitreal corticosteroid implants have been developed. Dexamethasone intravitreal implant provides retinal drug delivery for 6 months and recently has been approved for use in the treatment of DME. Pooled findings (n=1,048) from two large-scale, randomized Phase III trials indicated that dexamethasone intra- vitreal implant (0.35 mg and 0.7 mg) administered at 6-month intervals produced sustained improvements in best-corrected visual acuity (BCVA) and macularedema. Significantly more patients showed a 15-letter gain in BCVA at 3 years with dexamethasone intravitreal implant 0.35 mg and 0.7 mg than with sham injection (18.4% and 22.2% vs 12.0%). Anatomical assess- ments showed rapid and sustained reductions in macularedema and slowing of retinopathy progression. Phase II study findings suggest that dexamethasone intravitreal implant is effec- tive in focal, cystoid, and diffuse DME, in vitrectomized eyes, and in combination with laser therapy. Ocular complications of dexamethasone intravitreal implant in Phase III trials included cataract-related events (66.0% in phakic patients), intraocular pressure elevation 25 mmHg (29.7%), conjunctival hemorrhage (23.5%), vitreous hemorrhage (10.0%), macular fibrosis (8.3%), conjunctival hyperemia (7.2%), eye pain (6.1%), vitreous detachment (5.8%), and dry eye (5.8%); injection-related complications (eg, retinal tear/detachment, vitreous loss, endophthalmitis) were infrequent (2%). Dexamethasone intravitreal implant offers a viable treatment option for DME, especially in cases that are persistent or treatment (anti-vascular endothelial growth factor/laser) refractory.
Abstract: Diabeticmacularedema (DME) remains one of the leading causes of moderate to severe vision loss. Although laser photocoagulation was the standard of care for several years, few patients achieved significant improvements in visual acuity. As a result, several pharmacotherapies and surgeries have been investigated. The fluocinolone acetonide devices are one of the latest therapies considered for the treatment of DME. Despite bringing significant improvements in visual acuity, fluocinolone devices are associated with cataract formation, increased intraocular pressure (IOP), and surgery to lower IOP. Due to the risk of complica- tions, fluocinolone acetonide devices should be considered only in cases refractive to first-line therapies. In this review, we evaluate current and emerging therapies for DME, with special emphasis on fluocinolone acetonide intravitreal devices.
a number of strengths, including the adherence to international guidelines for performing indirect ana- lyses, inclusion of prespecified inclusion and exclusion criteria, and comprehensive assessment of clinical and statistical heterogeneity, it does have a number of limi- tations inherent with indirect analyses, the scope is nar- row, and the conclusions must be interpreted with caution. Many studies had unclear or high risk of bias in at least one domain of the Cochrane risk of bias tool, and safety outcomes were limited by differences in definitions of events. The number of events reported across studies was low, and the CIs were wide. There is a need for more studies comparing the relative effects of licensed therapies for DME in order to select the best treatment options for our patients; however, the findings from this indirect analysis are comparable to those published in the Protocol T study, which directly compared IVT-AFL with other anti-VEGF agents in patients with DME.
Trial participants were 30 consecutive, consenting patients with newly diagnosed ischemic DME. Inclusion and exclusion criteria are listed in Table 2. BCVA was recorded as number of letters + 30 read on an ETDRS chart at 4 m, or if no letters could be read at 4 m, then the number of let- ters read at 1 m. BCVA was recorded at baseline and then every 6 weeks for 30 weeks. A slit lamp examination was performed at each visit to look for any complications of the treatment. A spectral-domain optical coherence tomography (SD-OCT) scan was performed using Heidelberg Spectralis (Spectralis OCT, Heidelberg Engineering, software Version 22.214.171.124) to measure CST in microns at baseline and every 6 weeks. Fundus fluorescein angiography was performed using the Heidelberg Retina Angiograph II (HRA 2), at baseline and then at the third, fifth, and final visits to assess the size of the FAZ. The 45 second (or closest usable) fundus fluorescein angiography image (Figure 1) was used for the measurement of the FAZ. The image was exported to Adobe Photoshop for leveling to enable consistency between visits. The edges of the FAZ were demarcated and the area of isch- emia was calculated in terms of number of pixels.
tion of exudates and edema in these refractory cases was remarkable. Although the previous laser treatments might have had some beneficial effect, this may have been counter- acted by persistent vitreoretinal traction, on which laser treat- ment alone would have had no significant influence. Apart from relief of traction, induction of a PVD may also confer a secondary beneficial effect in increasing retinal oxygenation derived from the fluid phase between the neuroretina and the PHF. An increase in oxygen tension within the inner retina could have a mitigating effect on macularedema by a number of mechanisms: reduced VEGF production caus- ing decreased retinal vascular permeability; autoregulatory arteriolar vasoconstriction reducing hydrostatic pressure in capillaries and venules. There will be in turn decreased extravascular fluid flow (the Starling equation) and reduced edema formation. 18
tive DR and proliferative DR. Nonproliferative DR can be called as early stage and microaneurysm formation is the earliest sign of DR. Intraretinal hemorrhages, hard exudates, retinal capillary nonperfusion, cotton wool spots, venous abnormalities, and intraretinal microvascular abnormalities can be found during this stage. Proliferative DR, advanced stage, is characterized by neovascularization and develops due to isch- emia and release of vasoactive materials. These fragile, abnormal new vessels grow along the retina and into the vitreous, and lead to vitreous hemorrhage, tractional retinal detachment, resulting in vision loss. The most frequent cause of visual impairment in DR is due to diabeticmacularedema (DME), which occurs with leakage of plasma and lipid in the macula. 3 It can occur in any of the DR stages and in any patients with
After a 6-month observation period, 6 patients were diagnosed with DME of a mostly tractional character. In these patients only a minimal effect was observed after IVTA, so pars plana (PP) vitrectomies were performed, combined with phacoemulsification. In 17 other patients, IVTA was repeated after 6 months due to recurrent DME; 5 of these developed cataracts and the IVTA was com- bined with phacoemulsification. In 6 patients IVTA was repeated 4 times, and in 1 patient 5 times. In patients with recurrent DME after repeated IVTA, fluorescein angiog- raphy was carried out and compared with pretreatment images. In 5 such patients avascular zones, which were not covered by laser spots, were found in the periphery of the retina. This observation supports some suggestions from other authors that macularedema is caused by vas- cular endothelial growth factor (VEGF) from ischemia in the peripheral retina. 17 The ETDRS guidelines do not rec-
Results: Twenty-eight percent of patients had an anatomical response after the first course of IVB. Systemic hypertension (odds ratio, 95% confidence interval: 12.1, 0.7–21) was a statisti- cally significant predictor (P=0.025) of a good response to IVB, whereas previous macular laser was a statistically significant (P= 0.0005) predictor of a poor response (0.07, 0.01–0.32). Sixty-eight percent of eyes underwent subsequent treatment for DME after the first course of IVB. The visual acuity gain at 24 months in hypertensive (0.7 ± 3.6 letters) and nonhypertensive (5.2±3.7 letters) patients was not significantly different (P=0.41).
Several real-life studies have shown similar results regarding the number of retreatments during the ﬁ rst year and a mean duration between retreatment intervals. In a retrospective multicenter analysis of 79 eyes with DME treated with DEX implant and followed for at least 1 year after the ﬁ rst injection,38 72% of eyes did not require any additional treatment during the follow-up period. However, 21.5% of eyes required additional treatment before 6 months. The Chart Review of Ozurdex in MacularEdema study (CHROME) evaluated real-world use, ef ﬁ cacy, and safety of DEX implant in eyes with macularedema resulting from diabetes, retinal vein occlu- sion, and uveitis. The study included eyes receiving two or three DEX implant injections. The mean time to the ﬁ rst and second DEX implant reinjection in DME eyes was 5.8 ±0.5 months and 5.6±1.0 months, respectively. 41 Aknin and Melki reported that 47% of patients needed one, two, or three additional DEX implant injections in the follow-up period of 18 months, with a mean reinjection interval of 5.6 months. 81 Data from three studies in France showed consistent results regarding the use of DEX implant in DME patients with an average of 2.4 injections per year and 4.9 months interval between retreatments. 82 Escobar-Barranco et al reported a median time of 4 months for the ﬁ rst and the second reinjection. 39 Matonti et al observed that patients that received the second injection before the 5th month bene ﬁ ted from 9.9 letters more of visual gain at 12 months compared to patients retreated later than at the 5th month. At the baseline, there were only 0.6 letters of difference between these subgroups. 83 Similarly, Sarao et al reported a difference of 0.11 logMAR in BCVA after 6 months in favor of the group of DME eyes treated with the PRN regimen in comparison to the group of DME eyes that received DEX implant only at baseline. The mean number of injections in the PRN group was 1.6 in 6 months. 80 A recent systematic review of real-world studies done by Bucolo et al showed that the average mean retreatment time was 5.3±0.9 months. Retreatment was considered on a PRN basis at any time or starting from the 3rd or 4th month. 44 The idea of a ﬁ xed regimen with a shorter interval of reinjections was evalu- ated in a prospective, multicenter, randomized clinical
The VIVID-East study demonstrated the ef ﬁ cacy and safety of IVT-AFL for treating DME in Asian patients, including a large subgroup of Chinese patients, the largest subgroup represented in this study. Findings con ﬁ rm that the treatment bene ﬁ ts of IVT-AFL are similar in Asian patients with DME from China, Russia, the Republic of Korea, and Hong Kong compared with the overall populations of the previously conducted VIVID and VISTA phase 3 studies. 6 – 8 Numerical improvement in BCVA was seen as early as week 4 (the ﬁ rst post-treatment time point) with IVT-AFL 2q4 and 2q8. By week 20, BCVA had improved by a mean of 10.0 and 10.3 letters in the 2q4 and 2q8 groups, while the laser group had the largest improvement at week 12 (2.1 letters) and then slowly declined through to week 52. The improvements in the IVT-AFL groups increased further through week 52. The numerical values for the mean change in BCVA at week 52 in the VIVID-East treatment groups were +13.6 (2q4) and +13.1 (2q8) letters, compared with +12.5 (2q4) and +10.7 letters (2q8) in VISTA, 6 +10.5 (2q4) and +10.7 letters in VIVID. 6 The reasons for slightly differ- ent numerical outcomes are varied, and may include a younger mean age at study entry (58.5 years in the VIVID- East study and 63.6 years in the VIVID study) or differences in mean baseline BCVA with 55.9 and 60.1 letters observed in the VIVID-East and VIVID studies, respectively. In addi- tion, >60% of Asian patients achieved a ≥ 2-step improve- ment in DRSS score at week 52. There was a robust and rapid reduction of CRT in both IVT-AFL groups, with signi ﬁ cant improvements over the laser group. Again, this improvement was seen as early as week 4.
Olk in 1986 has demonstrated that visual acuity was stabilized in 60.9%, deteriorated in 24.6%, and improved in only 14.5% of the eyes with DME after MGP alone. Also, the treated eyes showed a high percentage of recurrence or persistence of macularedema despite appropriate macular laser therapy . The mild improvement after focal laser photocoagulation alone for DME has prompted interest in other treatment modalities, including intravitreal triamcinolone acetonide, intravitreal antibodies directed against vascular endothelial growth factor (VEGF) and pars plana vitrectomy .
Methods: Retrospective, interventional study examining patients with symmetric bilateral, center-involved DME recalcitrant to treatment with RZB, who received DEX in one eye while the contralateral eye continued to receive RZB every 4–5 weeks for a study period of 3 months. Results: Eleven patients (22 eyes) were included: mean logarithm of the minimal angle of resolution (logMAR) visual acuity (VA) for the DEX arm improved from 0.415 (standard devia- tion [SD] ±0.16) to 0.261 (SD ±0.18) at final evaluation, and mean central macular thickness (CMT) improved from 461 µm (SD ±156) to 356 µm (SD ±110; net decrease: 105 µm, P=0.01). Mean logMAR VA for the RZB arm improved from 0.394 (SD ±0.31) to 0.269 (SD ±0.19) at final evaluation. Mean CMT improved from 421 µm (SD ±147) to 373 µm (SD ±129; net decrease: 48 µm, P=0.26).
Abstract: Diabeticmacularedema (DME) has shown an increasing prevalence during the past years and is the leading cause of diabetic retinopathy blindness. Traditional treatment modalities include laser and corticosteroid therapy, which, however, either act through unclear mechanisms or cause cataracts and elevated intraocular pressure. In recent years, as the pathogenic role of VEGF in DME has been well-recognized, the intravitreal injection of anti-VEGF drugs has become the first-line treatment of DME due to their great efficacy in improving visual acuity and mitigating macularedema. Advantages have been shown for aflibercept and conbercept, the two recombinant decoy receptors that can bind VEGF with high specificity and affinity, in DME treatment in clinical trials conducted both worldwide and in People’s Republic of China. This review introduces the structural characteristics and molecular mechanisms of action of these two anti-VEGF drugs, and summarizes the clinical trials evaluating their efficacy and safety, with the hope to provide clues for designing optimal and personalized therapeutic regimens for DME patients.
2015. The inclusion criteria were the presence of DME before therapy (FT at baseline ≧ 300 microns) and no history of ocular surgery (including laser) and/or other treatment for macularedema within the previous 10 weeks. No patients were treated with a dexametha- sone implant because the treatment has not yet been approved in Japan. No patients had a history of intravit- real anti-VEGF therapy. The exclusion criteria were the logarithm of the minimum angle of resolution (logMAR) VA below 0 (20/200, Snellen equivalent). The patients underwent comprehensive ophthalmologic examinations including measurement of the best-corrected VA (BCVA), slit-lamp biomicroscopy with a noncontact fundus lens, and spectral-domain optical coherence tomography (SD-OCT) (RetinaScan RS-3000, Nidek, Gamagori, Japan). The BCVA was measured using a standard Japanese decimal VA chart at 5 m. The decimal values were converted to logMAR units for statistical analyses. To evaluate the FT, the macular map analysis protocol of the RS-3000 SD-OCT was used. The FT was defined as the average of all points in the inner circle (radius of 1 mm) at the center of the nine sectors defined by the Early TreatmentDiabetic Retinopathy Study grid .
Inclusion criteria included ability to provide writ- ten informed consent, age 18 years or older, adequately clear media for SD-OCT imaging, and Snellen visual acuity of 20/40 to 20/300 in the study eye. Anatomic cri- teria for inclusion required CRT ≥ 350 μm on SD-OCT and recalcitrant DME was defined as persistent cystic change with ≤15% decrease in CRT over the 6 months prior to IAI switch despite having at least 4 total treat- ments for DME, with at least 3 of these treatments being intravitreal anti-VEGF injections (excluding IAI). Treat- ments for DME prior to IAI switch included intravitreal bevacizumab (IVB) and ranibizumab (IVR), intravitreal triamcinolone acetonide (IVTA), sub-Tenon’s triamci- nolone acetonide (STTA), dexamethasone intravitreal implant (Ozurdex; Allergan, Irvine, California), and laser photocoagulation. If both eyes of a patient met entry criteria, then the worse-seeing eye was included in the study. If patients were treated with previous cor- ticosteroids, baseline intraocular pressure had to be 21 mm Hg or less either with or without pressure reduc- ing drops. Those patients who were previously treated with corticosteroids also had to have adequate clar- ity of media to allow adequate SD-OCT image quality. Patients were excluded if they had previously received intravitrealaflibercept in the study eye or a history of systemic anti-VEGF therapy. Inclusion and exclusion criteria are outlined in Table 1.
Abstract: Neovascular age-related macular degeneration (AMD) and diabeticmacularedema (DME) are major causes of visual impairment in the elderly population worldwide. With the aging population, the prevalence of neovascular AMD and DME has increased substantially over the recent years. Vascular endothelial growth factor (VEGF) has been implicated as playing an important role in the pathogenesis of both neovascular AMD and DME. Since its introduction in 2006, ranibizumab, a recombinant, humanized, monoclonal antibody fragment against all isoforms of VEGF-A, has revolutionized the treatment of neovascular AMD and DME. The efficacy and safety of ranibizumab in neovascular AMD has been demonstrated in the ANCHOR and MARINA trials. Further studies including the PIER, PrONTO, and SUSTAIN trials have also evaluated the optimal dosing regimen of ranibizumab in neovascular AMD. The CATT and IVAN trials compared the safety and efficacy of ranibizumab with off-label use of bevacizumab. Studies such as SUSTAIN and HORIZON have shown that ranibizumab has a good safety profile and is well tolerated for over 4 years with very few serious ocular and systemic adverse events. For DME, Phase II RESOLVE study and Phase III RISE and RIDE studies have demonstrated superiority of ranibizumabtreatment in improving vision over placebo controls. Phase II READ and Phase III RESOLVE and REVEAL studies have shown that ranibizumab is more effective both as monotherapy and in combination with laser compared with laser monotherapy. The 3-year results from the DRCRnet protocol I study found that ranibizumab with deferred laser resulted in better long-term visual outcome compared with ranibizumab with prompt laser. This review summarizes various important clinical trials on the long-term efficacy and safety of ranibizumab in the treatment of neovascular AMD and DME. The pharmacological properties of ranibizumab, its cost effectiveness, and impact on quality of life will also be discussed.
The analysis pursued is characterized by specific draw- backs and limitations. Since the analysis was undertaken from the perspective of Greek Health Care Insurance Fund, only direct medical costs for the treatment of VI due to DME were considered. Notwithstanding, it is acknowledged that the ramifications of a DME have a wider impact generating significant indirect costs (e.g. productivity losses) that could enhance the results of our analysis. A specific drawback regarding the adaptation of this cost-effectiveness model was the fact that, due to lack of Greek-specific studies, DME-related mortal- ity was assumed to be the same as in the UK core model. Another limitation of the study was the fact that it did not account for variation in treatment practice (i.e. the num- ber of injections in year 1–3 was tested). Moreover, the clinical inputs of the current study were extracted from a network meta-analysis and not a head to head study. Finally, within the context of customization, it should be noted that the results refer strictly to Greece and on the basis of the present time resource and drug prices. If any